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. 2026 Aug 24;43(4):345–354. doi: 10.5114/ada.2026.164292

Short-term risk and long-term incidence rate of herpes zoster with upadacitinib in patients with atopic dermatitis and psoriatic arthritis: a systematic review and meta-analysis

Zhimin Wang 1, Lu Xue 1, Quan Zhou 1, Huiying Li 1, Shangyi Meng 1, Huiping Wang 1,✉
PMCID: PMC13670913  PMID: 42890071

Abstract

Introduction

Upadacitinib is a novel selective Janus kinase 1 (JAK1) inhibitor. However, it increases the risk of herpes zoster infection.

Aim

We aimed to estimate the short-term risk and long-term incidence rate of herpes zoster in patients with atopic dermatitis (AD) and psoriatic arthritis (PsA) treated with different doses of upadacitinib.

Methods

Randomised controlled trials and long-term (≥ 52 weeks) open-label extension studies of upadacitinib for AD and PsA were included. Short-term odds ratios (ORs) and long-term exposure-adjusted event rates (EAERs) for herpes zoster infection were estimated using R software 4.4.3 and STATA 18.0.

Results

This review included 8 randomised controlled studies and 11 open-label extension studies. The short-term analysis showed that in AD patients, the ORs for herpes zoster infection after 15 mg and 30 mg upadacitinib were 2.62 (95% CI: 1.06–6.47) and 3.13 (95% CI: 1.38–7.12), respectively. In PsA patients, the ORs were 1.39 (95% CI: 0.45–4.33) and 2.43 (95% CI: 0.96–6.16), respectively. The long-term analysis showed that the EAER for herpes zoster infection in AD and PsA patients using 15 mg upadacitinib was 1 year: 3.87/100 patient-years (PYs), 2 years: 4.68/100 PYs, and 3 years: 4.30/100 PYs; for 30 mg, the EAER was 1 year: 6.96/100 PYs, 2 years: 8.29/100 PYs, and 3 years: 7.53/100 PYs. Upadacitinib 30 mg was associated with a significantly higher risk of herpes zoster compared with 15 mg, with consistent dose-dependent effects at 1-year (OR = 1.78, 95% CI: 1.41–2.24), 2-year (OR = 1.80, 95% CI: 1.28–2.53), and 3-year follow-up (OR = 1.94, 95% CI: 1.59–2.35).

Conclusions

Upadacitinib increases the risk of herpes zoster in AD and PsA patients, with a more significant effect in AD patients and a dose-dependent relationship over time.

Keywords: atopic dermatitis, psoriatic arthritis, herpes zoster, Upadacitinib

Introduction

Immune-mediated skin diseases, such as psoriasis/psoriatic arthritis (PsA) and atopic dermatitis (AD), affect a considerable portion of the population [1]. The Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway is a key component in the pathogenesis of various immune-mediated diseases. Multiple pro-inflammatory cytokines exert their pathological functions through this intracellular signalling pathway [2]. The JAK family is composed of JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). JAK inhibitors, as small-molecule targeted drugs with rapid onset of action and multi-target advantages, have gradually been widely used in clinical practice, showing good therapeutic effects [3]. Upadacitinib, as a selective JAK1 inhibitor, has been approved by the FDA for the treatment of various chronic inflammatory diseases, including moderate to severe rheumatoid arthritis, PsA, AD, ankylosing spondylitis, Crohn’s disease, and ulcerative colitis [4–9]. To date, in the dermatology field, upadacitinib has been approved only for the treatment of AD and PsA.

Herpes zoster is a viral infection caused by the reactivation of the varicella-zoster virus in individuals who have previously been infected with chickenpox. It is typically characterised by painful blisters with a unilateral distribution and can lead to severe complications, including postherpetic neuralgia [10]. The incidence of herpes zoster increases with age and is further elevated in autoimmune diseases [11]. Studies have shown that the use of JAK1 selective inhibitors, such as upadacitinib and abrocitinib, significantly increases the risk of herpes zoster [12]. However, the specific characteristics of this risk, including short-term and long-term risks, dose dependence, and variations in different immune-mediated dermatological conditions, remain insufficiently clarified. Understanding these risk characteristics is crucial for guiding clinical treatment in dermatology.

Aim

Therefore, this study aims to systematically evaluate and perform a meta-analysis to assess the short-term risk and long-term incidence of herpes zoster associated with different doses of upadacitinib in the treatment of AD and PsA patients.

Methods

Study design and systematic literature search

According to the PRISMA guidelines, this study is designed as a systematic review and meta-analysis. A predefined protocol (PROSPERO registration number CRD420261277770) was used for literature search, study selection, quality assessment, data extraction, and statistical analysis. Randomised controlled trials and long-term extension studies on upadacitinib for the treatment of AD and PsA were searched in PubMed, Embase, Cochrane Library, and Web of Science. The search strategy included Medical Subject Headings (MeSH) or Emtree terms, with a search cutoff date of 5 January 2026. The search terms included “upadacitinib” and “atopic dermatitis or psoriatic arthritis”. Only English-language publications were included. The detailed search strategy and results are summarised in the supplement (Supplementary Material S1). A manual search of the reference lists of included studies was conducted to obtain additional literature.

Eligibility criteria

Inclusion criteria

The inclusion criteria for the literature were defined according to the PICOS (Population, Intervention, Comparison, Outcomes, and Study) method: Population (P): Adolescents and adults with AD and PsA. Intervention (I) and Comparison (C): Oral upadacitinib 15 mg once daily vs. placebo; oral upadacitinib 30 mg once daily vs. placebo; oral upadacitinib 15 mg once daily vs. oral upadacitinib 30 mg once daily. Outcomes (O): Short-term and long-term incidence of herpes zoster as an adverse event. Study (S): Published randomised controlled trials and long-term extension studies.

Exclusion criteria

The exclusion criteria for this study are as follows: (1) Studies for which the full text is not available. (2) Studies that do not report original data, have incomplete outcome data, or cannot be included in statistical analysis. (3) Duplicate publications. (4) Non-English language publications. (5) Reviews, conference abstracts, case reports, cohort studies, case-control studies, and non-clinical studies such as animal or cell studies.

Study selection and data extraction

Two independent researchers screened the titles and abstracts of potentially eligible studies. The remaining studies were then subjected to full-text review to determine whether they met the inclusion criteria. Any disagreements between the researchers regarding the inclusion of studies were resolved through discussion with a third researcher.

For the included studies, the following information was collected: authors, publication year, trial name, ClinicalTrials.gov identifier, study design and phase, disease type, and age of the included population. For randomised controlled trials (RCTs), the following data were extracted: treatment dose, duration, number of patients in the treatment and placebo groups, and the number of herpes zoster infections in each group. For open-label extension (OLE) studies, the following data were extracted: treatment dose, duration of the open-label extension period, number of patients in each group, total patient-years (PYs) of exposure, number of herpes zoster infections, exposure-adjusted event rate (EAER) for herpes zoster infections, and their 95% confidence intervals (CIs). Data extraction was performed independently by two researchers. Any discrepancies were resolved through discussion with a third researcher.

Quality evaluation

The risk of bias was assessed by two independent researchers. For eligible RCT studies, the Cochrane risk-of-bias tool was used to evaluate the randomisation of the interventions. Disagreements were resolved through consultation with a third researcher. The overall risk of bias was categorised into three levels: low risk of bias, unclear risk of bias, and high risk of bias. The results were summarised and presented using Review Manager 5.4.1.

Statistical analysis

The number of herpes zoster infections in the intervention and control groups was recorded from eligible studies. The odds ratio (OR) was calculated based on the number of infected patients and the total number of patients in each group. The OR and its 95% CI for each outcome were combined, and each result was presented using a forest plot. Heterogeneity was tested using the I2 test and the Q test. Both fixed-effect and random-effect models were calculated. If I2 ≥ 50%, the random-effect model was used. Subgroup analyses were performed based on disease type. For OLE studies, stratification by year was conducted. Funnel plots and trim-and-fill methods were used to estimate publication bias. Sensitivity analysis was performed to assess the consistency and robustness of the results. Statistical analysis was conducted using R software version 4.4.3 and the ‘meta’ package. A p-value less than 0.05 was considered statistically significant.

The long-term incidence of herpes zoster infections was determined by exposure-adjusted event rates (EAERs) with 95% CIs, calculated as events per 100 patient-years (PYs). If the original studies did not provide the data, the 95% CI was calculated based on the Poisson distribution. Data for durations of 1 year, 2 years, and 3 years were included in the analysis. Patients receiving 15 mg/30 mg doses of upadacitinib were included in the final analysis. A combined estimate of the EAER for each outcome was performed, and the results were presented using forest plots. The results were stratified by year to determine the EAER for different treatment durations. Statistical analysis was performed using STATA 18.0 software. A p-value less than 0.05 was considered statistically significant.

Results

Search results and trial characteristics

A total of 1160 potentially relevant studies were identified through database search. After removing 471 duplicates, 689 records were screened, excluding 621 by title and abstract. Subsequent full-text review excluded another 52 reports (21 not retrieved, 31 ineligible). Ultimately, 16 studies and 19 reports met the inclusion criteria [13–28]. The flowchart of the literature selection is shown in Figure 1. Eight RCTs included a total of 5356 patients, and 11 OLE studies included a total of 9633 patients, with a total exposure of 18025.8 patient-years (PYs). Additional details and characteristics are presented in Supplementary Table S1.

Figure 1.

Figure 1

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Flowchart of the literature selection

Quality assessment of the included studies

Even when the blinding risk was unclear in some trials, the overall risk of bias was low. The Cochrane risk-of-bias assessment tool was used to evaluate the risk of bias in randomised studies of interventions. The detailed risk of bias for each included study is shown in Figure 2.

Figure 2.

Figure 2

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Risk of bias graph

Short-term risk

Eight RCTs included a total of 5356 patients, with 1859 in the 15 mg treatment group, 1870 in the 30 mg treatment group, and 1627 in the placebo group. The risk of herpes zoster with upadacitinib compared to placebo in different disease backgrounds: For PsA patients, the difference for herpes zoster infection in the 15 mg group was not statistically significant (OR = 1.39, 95% CI: 0.45; 4.33), while for AD patients, the difference was statistically significant (OR = 2.62, 95% CI: 1.06; 6.47), according to the forest plot (Figure 3). No subgroup difference was found between the two indications (p = 0.3926). For the 30 mg group, the difference for herpes zoster infection in PsA patients was not statistically significant (OR = 2.43, 95% CI: 0.96; 6.16), while for AD patients, the difference was statistically significant (OR = 3.13, 95% CI: 1.38; 7.12), according to the forest plot (Figure 4). No subgroup difference was found between the two indications (p = 0.6885). The risk of herpes zoster with 30 mg upadacitinib compared to 15 mg in different disease backgrounds: For PsA patients, the difference was not statistically significant (OR = 1.82, 95% CI: 0.75; 4.41), and for AD patients, the difference was not statistically significant (OR = 1.42, 95% CI: 0.72; 2.79), according to the forest plot (Figure 5). No subgroup difference was found between the two indications (p = 0.6607).

Figure 3.

Figure 3

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Pooled odds ratio (OR) of herpes zoster with the treatment of upadacitinib 15 mg vs. placebo

Figure 4.

Figure 4

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Pooled odds ratio (OR) of herpes zoster with the treatment of upadacitinib 30 mg vs. placebo

Figure 5.

Figure 5

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Pooled odds ratio (OR) of herpes zoster with the treatment of upadacitinib 30 mg vs. upadacitinib 15 mg Study Intervention Control Odds ratio OR 95% CI Weight (%)

Long-term incidence rates

Eleven studies reported OLE, with the EAER of herpes zoster infection in AD and PsA patients using 15 mg upadacitinib: 1 year 3.87/100 PYs, 2 years 4.68/100 PYs, and 3 years 4.30/100 PYs (Figure 6). No evidence was found to suggest an increase in the incidence of herpes zoster infection with prolonged treatment with 15 mg upadacitinib. The EAER of herpes zoster infection in AD and PsA patients using 30 mg upadacitinib: 1 year 6.96/100 PYs, 2 years 8.29/100 PYs, and 3 years 7.53/100 PYs (Figure 7). No evidence was found to suggest an increase in the incidence of herpes zoster infection with prolonged treatment with 30 mg upadacitinib. The risk of herpes zoster with 30 mg upadacitinib compared to 15 mg: 1 year (OR = 1.78, 95% CI: 1.41; 2.24), 2 years (OR = 1.80, 95% CI: 1.28; 2.53), and 3 years (OR = 1.94, 95% CI: 1.59; 2.35), with an increased risk of herpes zoster infection (Figure 8).

Figure 6.

Figure 6

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Pooled exposure-adjusted event rates (EAERs) of herpes zoster in AD and PsA patients receiving 15 mg upadacitinib treatment

Figure 7.

Figure 7

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Pooled exposure-adjusted event rates (EAERs) of herpes zoster in AD and PsA patients receiving 30 mg upadacitinib treatment

Figure 8.

Figure 8

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Pooled odds ratio (OR) of herpes zoster in AD and PsA patients receiving long-term upadacitinib 30 mg vs. upadacitinib 15 mg

Publication bias and sensitivity analyses

The funnel plots created for the above results were found to be approximately symmetric. The results of the trim and fill method showed that after trimming and recalculating the effect size, the statistical significance did not change. Sensitivity analysis using the leave-one-out method showed that, overall, the results were highly consistent in terms of effect direction and generally robust in terms of statistical significance (Supplementary Figure S1).

Discussion

Upadacitinib, a novel selective oral JAK1 inhibitor, has been approved for the treatment of various immune-mediated diseases, including AD and PsA [29]. However, its use is associated with an increased risk of infections, particularly herpes zoster [30]. This study aimed to comprehensively assess the risk of herpes zoster associated with the JAK inhibitor, upadacitinib in the treatment of AD and PsA patients through a systematic review and meta-analysis. Our analysis integrated data from both short-term RCTs and long-term OLE. The uniqueness of this analysis lies in its ability to reveal for the first time within the same study the short-term and long-term risks of herpes zoster related to upadacitinib, its dose-dependent nature, and the differences observed across various immune-mediated skin disease backgrounds. The results suggest that short-term data did not fully capture the dose-dependent nature, while long-term data clearly showed that the 30 mg dose posed a higher risk. Moreover, this risk persisted throughout long-term treatment without accumulating over time, and AD patients showed a significantly higher risk than PsA patients during short-term treatment.

The mechanism by which JAK inhibitors increase the risk of herpes zoster infection has not been fully elucidated. The JAK-STAT signalling pathway plays a key role in antiviral immune responses, particularly against herpesviruses. Specifically, JAK1 and JAK3 signalling pathways are critical for the maturation and survival of Th1, CD8+ cells, and B cells, which are key cells in the antiviral immune response. Inhibition of this pathway may lead to either primary infection or reactivation of latent viruses [31]. Even highly selective JAK inhibitors appear to affect the complex immune network, producing widespread effects [32]. Studies have shown that varicella-zoster virus infection blocks the JAK/STAT signalling pathway mediated by JAK1/Tyk2, and JAK1 inhibition may mimic its antiviral activity, increasing the risk of viral reactivation [33]. Furthermore, common risk factors for herpes zoster in the general population include age, female gender, race, smoking or alcohol abuse, genetic susceptibility, stress, and immunosuppression [34–36]. Autoimmune diseases themselves are also associated with an increased risk of varicella-zoster virus infection [37, 38]. The use of JAK inhibitors may have a cumulative or synergistic effect with these existing risks, further increasing the incidence of herpes zoster infection. Existing studies indicate that patients with autoimmune diseases receiving JAK inhibitors have a higher incidence of herpes zoster compared to those receiving placebo or immunomodulatory drugs [39].

In this study, it was found that in short-term RCTs, both the 15 mg and 30 mg dose groups showed a significantly higher risk in AD patients compared to the placebo group, while in PsA patients, although there was a trend towards increased risk, it did not reach statistical significance. This finding is consistent with previous studies suggesting that AD patients have a higher risk of herpes zoster when using JAK inhibitors, whereas in PsA patients, regardless of the type or dose of the JAK inhibitor used, no significant difference in herpes zoster infection risk was observed compared to the placebo group [40, 41]. This difference may be related to the immunopathological background of the disease itself and baseline characteristics of the patient population (such as age and history of prior immunosuppressive therapy). For example, AD patients are generally younger, but their impaired skin barrier function and reduced antimicrobial peptide expression may provide local conditions for viral reactivation. On the other hand, PsA patients are likely older and have a history of using traditional synthetic DMARDs, so their baseline risk of herpes zoster may already be higher. Other studies have also suggested that AD itself is a risk factor for herpes zoster infection, regardless of disease severity or treatment [42]. Even patients below the recommended age for herpes zoster vaccination are at increased risk. Among AD patients under the age of 50, the risk of herpes zoster is also increased [43]. However, the subgroup analysis in this study did not find a statistically significant difference in risk between the two diseases, indicating that current evidence is insufficient to conclude a fundamental disease-specific difference in risk. Further studies with larger sample sizes are needed to verify this.

In the long-term follow-up of up to 3 years, although the risk in the 30 mg dose group was consistently higher than in the 15 mg dose group, no evidence was observed indicating a significant cumulative increase in the risk of herpes zoster with prolonged treatment duration. A comprehensive safety analysis of upadacitinib showed that the EAERs of herpes zoster events remained stable over time across all indications [44]. This finding is consistent with the perspective presented in this study. It holds positive clinical significance, as it helps clinicians in managing long-term risks for patients, emphasising the need to pay special attention to the occurrence of herpes zoster events during the early stages of treatment with upadacitinib, while remaining vigilant throughout the entire treatment period.

It is noteworthy that in the short-term analysis of this study, no significant difference in the risk of herpes zoster was observed between the 15 mg and 30 mg dose groups, while long-term data showed a clear dose-dependent relationship. A network meta-analysis indicated that both 15 mg and 30 mg doses of upadacitinib were associated with an increased risk of herpes zoster, with a dose-dependent effect [12]. However, two other published studies suggested that the use of 15 mg or 30 mg upadacitinib was associated with an increased risk of herpes zoster, but this adverse event did not show a dose-dependent effect, with no statistical difference [45, 46]. There are differing views in existing studies, and this study, by distinguishing based on the duration of included studies, reached the opposite conclusion. This suggests that relying solely on short-term trial data of 12–16 weeks may underestimate the potential risks of high doses, and low-incidence events may be difficult to detect in short-term, limited sample sizes. Therefore, integrating long-term safety data is crucial for a comprehensive assessment of the dose-dependent risks of JAK inhibitors.

Previous articles have suggested that varicella-zoster virus (VZV) vaccination should be recommended for prophylactic vaccination before starting JAK inhibitor therapy [47]. Currently, two vaccines are available for the prevention of herpes zoster: the varicella-zoster virus live attenuated vaccine (ZVL) and the recombinant varicella-zoster virus vaccine (RZV). ZVL is not recommended during JAK inhibitor treatment, and it is instead recommended to start JAK inhibitor therapy at least 2–4 weeks after receiving the herpes zoster live attenuated vaccine [31]. The current National Health Service (NHS) guidelines in the UK recommend the use of RZV for individuals who have been receiving or have received targeted therapies such as JAK inhibitors or biologic treatments within the past 3 months [33]. The results of this study provide clear guidance for clinical practice. For patients planning to use upadacitinib, especially at higher doses or those with additional risk factors such as advanced age, clinicians should place a high emphasis on herpes zoster risk prevention. Before initiating treatment, patients should undergo risk assessments and, in accordance with domestic and international guidelines, those who are susceptible should receive the herpes zoster vaccine. Additionally, patient education should be enhanced to ensure they recognise the early symptoms of herpes zoster for timely diagnosis and treatment.

This study has several limitations. First, the number of included RCTs is limited, particularly with small sample sizes in certain subgroups (such as PsA patients), which may result in insufficient statistical power to detect real differences (i.e., type II error). Second, the OLE studies themselves lack parallel placebo-controlled groups, and their risk estimates primarily rely on internal dose comparisons, which may be influenced by factors such as patient selection bias. Lastly, this study did not quantify or analyse important confounding factors that may affect the risk of herpes zoster, such as patient age, vaccination history, and concomitant medications, which may not have been adequately reported in the original studies.

Future research should focus on identifying biomarkers or clinical predictors associated with a herpes zoster risk related to upadacitinib, enabling individualised risk prediction. Additionally, large-scale, long-term follow-up data from real-world settings are needed to further confirm risk differences across different populations and evaluate the effectiveness of preventive strategies.

In conclusion, this meta-analysis confirms that the use of upadacitinib is associated with an increased risk of herpes zoster, with a more clearly defined risk in AD patients. Long-term data indicate that this risk is persistent but non-cumulative. Clinicians should remain vigilant when using upadacitinib and adopt proactive prevention and management strategies to ensure the safety of patients.

Supplementary Material

PDIA-43-4-58512-s1.pdf (245.2KB, pdf)
PDIA-43-4-58512-s2.pdf (60.8KB, pdf)
PDIA-43-4-58512-s3.pdf (382.6KB, pdf)
PDIA-43-4-58512-s4.pdf (426.2KB, pdf)

Funding Statement

Funding This study was funded by Tianjin Key Medical Discipline Construction Project (No. TJYXZDXK-3-010C), Natural Science Foundation of Tianjin (No. 24JCZDJC00610) and Tianjin Health Research Project (No. TJWJ2023XK006).

Ethical approval

Not applicable.

Conflict of interest

The authors declare no conflict of interest.

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Supplementary Materials

PDIA-43-4-58512-s1.pdf (245.2KB, pdf)
PDIA-43-4-58512-s2.pdf (60.8KB, pdf)
PDIA-43-4-58512-s3.pdf (382.6KB, pdf)
PDIA-43-4-58512-s4.pdf (426.2KB, pdf)

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